Ok, who is looking into preventing inflammatory response in the brain and periphery? Only 7 years old so if we had a decent stroke association run by survivors we would have had followup research by now.
Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome
Abstract
Background
Cerebral ischaemia initiates an inflammatory response in the brain and periphery. We assessed the relationship between peak values of plasma interleukin-6 (IL-6) in the first week after ischaemic stroke, with measures of stroke severity and outcome.
Methods
Thirty-seven patients with ischaemic stroke were prospectively recruited. Plasma IL-6, and other markers of peripheral inflammation, were measured at pre-determined timepoints in the first week after stroke onset. Primary analyses were the association between peak plasma IL-6 concentration with both modified Rankin score (mRS) at 3 months and computed tomography (CT) brain infarct volume.
Results
Peak plasma IL-6 concentration correlated significantly (p < 0.001) with CT brain infarct volume (r = 0.75) and mRS at 3 months (r = 0.72). It correlated similarly with clinical outcome at 12 months or stroke severity. Strong associations were also noted between either peak plasma C-reactive protein (CRP) concentration or white blood cell (WBC) count, and all outcome measures.
Conclusions
These data provide evidence that the magnitude of the peripheral inflammatory response is related to the severity of acute ischaemic stroke, and clinical outcome.
Keywords:
stroke acute; interleukin-6; C-reactive protein; inflammation; outcome measuresBackground
Cerebral ischaemia initiates an inflammatory response in the brain [1] that is associated with induction of a variety of cytokines, including interleukin-6 (IL-6), a pleiotropic cytokine involved in diverse inflammatory functions. IL-6 mRNA and bioactivity are induced rapidly in experimental focal cerebral ischaemia [2,3], and elevated IL-6 concentrations in cerebrospinal fluid (CSF) of acute stroke patients correlate with infarct volume [4]. However, the role of IL-6 in the central nervous system (CNS) following experimental cerebral ischaemia is not resolved [2,3,5,6].
Systemic inflammatory responses are also evident following inflammation in the CNS, but the relationship between peripheral mediators and CNS events is uncertain [7]. Peripheral infection, which commonly precedes or complicates stroke [8,9], is also a major stimulus for production of cytokines and an acute phase response. Although most cytokines are only present at biologically effective concentrations at the site of inflammation, IL-6 is a major circulating cytokine produced in response to inflammatory insult and infection, and is a potent stimulus for production of hepatic acute phase proteins [10], induction of fever [11], and activation of the hypothalamic-pituitary-adrenal (HPA) axis [12].
The relationship between peripheral inflammatory markers and outcome in stroke patients remains poorly understood. In patients with acute ischaemic stroke, some studies have reported an association between circulating IL-6 concentration and brain infarct volume, stroke severity, or outcome up to 6 months [13-17]. Conversely, other studies have reported no association between serum IL-6 concentration and infarct volume or stroke severity at 3 months [4,18]. Other markers of the acute phase response have also been implicated in the pathophysiology and outcome following ischaemic stroke [19-26]. However, very few studies have related the magnitude of the peripheral inflammatory response in the first week to measures of severity of ischaemic insult or clinical outcome.
We have recently reported the kinetics of peripheral inflammatory markers in ischaemic stroke patients prospectively recruited within 12 hours of symptom onset, compared to controls matched for age, sex and degree of atherosclerosis [27]. The aim of the present study was to examine the relationship between the magnitude of the peripheral inflammatory response, as determined by peak values of plasma IL-6 or other peripheral inflammatory markers (peak plasma C-reactive protein (CRP), white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), plasma cortisol concentration and aural temperature) in the first week of stroke, with either severity of ischaemic insult, or long-term outcome.
Subjects and methods
The study was approved by the Local Research Ethics Committee. Consecutive patients aged over 18 years presenting with a clinical diagnosis of acute stroke, with suspected symptom onset within the preceding 12 hours, were screened prospectively. Patients were excluded if the time of symptom onset could not be reliably determined from the patient or witness. Patients with rapid improvement of symptoms between onset and screening, or evidence of active malignancy, were also excluded. Written informed consent was obtained from all patients recruited, or written assent from a relative. Clinical history, examination, medications and Oxfordshire Community Stroke Project (OCSP) classification [28] were recorded at baseline. Computed tomography (CT) brain scan (IGE CT Pace Plus 3rd generation scanner, IGE Medical Systems Ltd, Milwaukee, WI) was performed within 24 hours of admission to exclude patients with stroke mimic or primary intracerebral haemorrhage (PICH). Blood pressure, pulse rate and aural temperature (Braun Thermoscan LF20 digital thermometer) were recorded at all visits. At 3 and 12 months, additional medical history, changes in medication history and general clinical examination were also recorded. Infections were recorded prospectively during the study period wherever possible, using all available clinical information and investigation results. In the case of suspected infections preceding the index stroke, information was gathered from history and clinical records.
Blood sampling and determination of peripheral inflammatory markers
Venous blood was drawn by venepuncture at study entry, next day at 09:00, 24 hours (if presentation was not between 07:00 and 11:00) and 5 to 7 days. Blood was collected in tubes containing EDTA (Sarstedt, UK) for analysis of ESR using an automated Westergren method (Starrsed 3, Mechatronics, Holland; supplied by Vitech Scientific, UK) and total WBC count using the Coulter principle method (Beckman-Coulter GEN-S, Florida, USA). The remaining blood for plasma IL-6, CRP and cortisol analysis was transferred to heparinised tubes, stored in cooled gel packs for one hour, and centrifuged at 2000 g for 30 minutes at 4°C. Plasma was separated, frozen and stored at -70°C until analysis. Plasma IL-6 was measured using a sandwich enzyme-linked immunosorbent assay (ELISA), plasma CRP using a competitive, high-sensitivity ELISA, and plasma cortisol using a solid phase time-resolved fluroimmunoassay (DELFIA®, Perkin Elmer™ Life Sciences, manufactured by Wallac Oy, Finland) described in detail elsewhere [27].
Definition of peak values
For individual patients, the peak value for each peripheral inflammatory marker was defined as the maximum measured value between presentation and 5 to 7 days. Patients who died prior to 5 to 7 days, or for whom data were missing, were therefore not assigned a peak value and were excluded from further analysis.
Assessment of stroke severity and outcome
Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score [29] at presentation and 5 to 7 days. Functional status during the four weeks preceding the index stroke was recorded using the modified Rankin score (mRS) [30] and Barthel index (BI) [31] at presentation. Subsequent functional outcome was assessed using the mRS and BI at 3 and 12 months, derived either directly from evaluation of the patient or discussion with carers and relatives, or by telephone. Patients were contacted prior to the 3 and 12 month follow up periods for arrangement of hospital or home visits where necessary. All-cause mortality was recorded from death certificates and hospital records.
Measurement of CT brain infarct volume
A second CT brain scan for volumetric analysis was performed at 5 to 7 days, in order to minimise the "fogging" effect seen in the second to third weeks after ischaemic stroke [32]. Five to seven day CT brain scans and plasma sampling were performed on the same day, except in five cases where plasma was sampled, and CT scans performed, within 24 hours of each other.
The area of visible recent infarction on each digitised slice was traced manually with a cursor, the volume of infarction was automatically calculated by the scanner volumetry program based on the areas measured, slice thickness and number of slices. For each 5 to 7 day scan with visible recent infarction, the mean of five observers' (CJS, HCAE, CML and two consultant neuroradiologists; DGH and IWT) independent infarct volume measurement was determined.
Statistical analysis
Pre-determined primary analyses were the association between peak plasma IL-6 concentration in the first week of ischaemic stroke, with either CT brain infarct volume, or mRS at 3 months. Secondary analyses explored the relationships between (1) peak plasma IL-6 concentration with stroke severity, BI at 3 months or outcome at 12 months, and (2) other peripheral inflammatory markers in the first week of ischaemic stroke and stroke severity, CT brain infarct volume or clinical outcome.
For the pre-determined primary analyses, significance was set at the 0.05 level. Data from the large number of secondary analyses are descriptive only, and used for the purpose of hypothesis generation. Statistical analyses were performed using SPSS® for Windows, version 10. Categorical data were summarised as frequencies and percentages. Continuous data were summarised as median (minimum, maximum). Non-parametric analyses were used throughout as the inflammatory markers were not normally distributed, and outcome measures were ordinal scales. Use of non-parametric methods allowed extension of scoring for outcome scales to incorporate death as the "worst outcome" possible. This prevented bias from exclusion of patients who died during study follow up. The relationship between inflammatory markers and outcome measures was determined using Spearman rank correlation. The Kaplan-Meier technique and log-rank test were applied in analysis of survival for patients with values above and below the median of peak plasma IL-6 concentration.
Results
Thirty-seven patients with ischaemic stroke were recruited between April 2000 and January 2001. Baseline characteristics and medications for the 37 patients at entry are presented in Table 1. Median (minimum, maximum) time from onset of stroke symptoms to recruitment was 5 (1.5 to 11.75) hours. Stroke characteristics and outcome measures are presented in Table 2. The number of patients at each visit is outlined in Figure 1. Two patients had documented infections (both respiratory), and one, a proven myocardial infarction within the six weeks preceding their index stroke. A further 7 had definite infections (four respiratory, two urinary and one peripheral cannula site), within the first week after the index stroke. One other patient developed sepsis during the first week, with no focus identified. Three patients died prior to the 5 to 7 day assessment (including the patient with the preceding myocardial infarction) leaving 34 patients with peak values of plasma IL-6, CRP, cortisol and aural temperature for analysis. Peak WBC count values were available in 32, and peak ESR in 27 of these patients. Of the fourteen patients (38%) who died by 12 months, causes of death were certified as index stroke in eight, recurrent stroke in one, sepsis in three, pulmonary embolus in one, and left ventricular failure secondary to preceding myocardial infarction in another.
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